Bile acids promote the caveolae-associated entry of swine acute diarrhea syndrome coronavirus in porcine intestinal enteroids.

Intestinal microbial metabolites have been increasingly recognized as important regulators of enteric viral infection. However, very little information is available about which specific microbiota-derived metabolites are crucial for swine enteric coronavirus (SECoV) infection in vivo. Using swine acute diarrhea syndrome (SADS)-CoV as a model, we were able to identify a greatly altered bile acid (BA) profile in the small intestine of infected piglets by untargeted metabolomic analysis. Using a newly established ex vivo model-the stem cell-derived porcine intestinal enteroid (PIE) culture-we demonstrated that certain BAs, cholic acid (CA) in particular, enhance SADS-CoV replication by acting on PIEs at the early phase of infection. We ruled out the possibility that CA exerts an augmenting effect on viral replication through classic farnesoid X receptor or Takeda G protein-coupled receptor 5 signaling, innate immune suppression or viral attachment. BA induced multiple cellular responses including rapid changes in caveolae-mediated endocytosis, endosomal acidification and dynamics of the endosomal/lysosomal system that are critical for SADS-CoV replication. Thus, our findings shed light on how SECoVs exploit microbiome-derived metabolite BAs to swiftly establish viral infection and accelerate replication within the intestinal microenvironment.

Hyperelatolides A-D, Antineuroinflammatory Constituents with Unusual Carbon Skeletons from Hypericum elatoides.

Four new δ- and γ-lactone derivatives, hyperelatolides A-D (1-4, respectively), were discovered from the aerial portions of Hypericum elatoides R. Keller. Their structures were elucidated by analysis of NMR spectra, HRESIMS, quantum chemical calculations of NMR and ECD spectra, and X-ray crystallographic data. Hyperelatolides A (1) and B (2) represent the first examples of δ-lactone derivatives characterized by a (Z)-(5,5-dimethyl-2-(2-oxopropyl)cyclohexylidene)methyl moiety and a benzoyloxy group attached to the ß- and γ-positions of the δ-lactone core, respectively, while hyperelatolides C (3) and D (4) are unprecedented γ-lactone derivatives featuring substituents similar to those of 1 and 2. All compounds were tested for their inhibitory effects on NO production in LPS-activated BV-2 cells. Lactones 1 and 2 exhibited considerable antineuroinflammatory activity, with IC50 values of 5.74 ± 0.27 and 7.35 ± 0.26 µM, respectively. Moreover, the mechanistic study revealed that lactone 1 significantly suppressed nuclear factor kappa B signaling and downregulated the expression of inducible nitric oxide synthase and cyclooxygenase-2 in LPS-induced cells, which may contribute to its antineuroinflammatory activity.

Hyperhubeins A-I, Bioactive Sesquiterpenes with Diverse Skeletons from Hypericum hubeiense.

Nine new sesquiterpenes, hyperhubeins A-I (1-9), and 14 known analogues (10-23) were isolated from the aerial portions of Hypericum hubeiense. Their structures and absolute configurations were determined unambiguously via spectroscopic analysis, single-crystal X-ray diffraction, and electronic circular dichroism calculations. Compounds 1-3 possess an unprecedented sesquiterpene carbon skeleton. Further, a plausible biosynthetic pathway from farnesyl diphosphate (FPP) is proposed. The isolated phytochemicals were evaluated for neuroprotective and anti-neuroinflammatory properties in vitro. Compounds 1, 2, 5-8, 14, and 21 displayed notable neuroprotective activity against hydrogen peroxide (H2O2)-induced lesions in PC-12 cells at 10 µM. Additionally, compounds 1, 2, 12, and 13 exhibited inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV-2 microglial cells, with their IC50 values ranging from 4.92 to 6.81 µM. Possible interactions between these bioactive compounds and inducible nitric oxide synthase (iNOS) were predicted via molecular docking. Moreover, Western blotting indicated that compound 12 exerted anti-neuroinflammatory activity by suppressing LPS-stimulated expression of toll-like receptor-4 (TLR-4) and inhibiting consequent activation of nuclear factor-kappa-B (NF-κB) signaling.

Longitudinal relationship between prosocial behavior and meaning in life of junior high school students: A three-wave cross-lagged study.

INTRODUCTION: Despite much cross-sectional research linking prosocial behavior and meaning in life, few studies have investigated the longitudinal relationship between these two constructs. The article examines the bidirectional longitudinal association between prosocial behavior and meaning in life among junior high school students. METHODS: A prospective design was adopted, incorporating three measurement occasions (with approximately 6-month intervals, from 2020 to 2021). Data were collected from 764 students (mean age = 12.46, SD = 0.64 years, and 51.4% girls). All participants responded to a questionnaire survey that included the Chinese Meaning in Life Questionnaire (MLQ-C) and Prosocial Tendencies Measure (PTM-C). Cross-lagged panel models were used to analyze the data. RESULTS: (1) Prosocial behavior predicted positively the presence of meaning over time and vice-versa. (2) There was no bidirectional association between the search for meaning and prosocial behavior. (3) There was no gender difference in the bidirectional relationship between meaning in life and prosocial behavior. CONCLUSIONS: These findings suggest that educators should highlight the presence of meaning in adolescent life education from a long-term perspective and encourage students to engage in more prosocial activities.

Ubiquitin-like protein FAT10 suppresses SIRT1-mediated autophagy to protect against ischemic myocardial injury.

Autophagy plays a deleterious role in ischemic myocardial injury. The deacetylase SIRT1 is a well-established regulator of autophagy that can be modified by the ubiquitin-like protein SUMO1. Our previous work demonstrated that another ubiquitin-like protein, FAT10, exerts cardioprotective effects against myocardial ischemia by stabilizing the caveolin-3 protein; however, the effects of FAT10 on autophagy through SIRT1 are unclear. Here, we constructed a Fat10-knockout rat model to evaluate the role of FAT10 in autophagy. In vivo and in vitro assays confirmed that FAT10 suppressed autophagy to protect the heart from ischemic myocardial injury. Mechanistically, FAT10 was mainly involved in the regulation of the autophagosome formation process. FAT10 affected autophagy through modulating SIRT1 degradation, which resulted in reduced SIRT1 nuclear translocation and inhibited SIRT1 activity via its C-terminal glycine residues. Notably, FAT10 competed with SUMO1 at the K734 modification site of SIRT1, which further reduced LC3 deacetylation and suppressed autophagy. Our findings suggest that FAT10 inhibits autophagy by antagonizing SIRT1 SUMOylation to protect the heart from ischemic myocardial injury. This is a novel mechanism through which FAT10 regulates autophagy as a cardiac protector.

The role of SOCS proteins in the development of virus- induced hepatocellular carcinoma.

BACKGROUND: Liver cancer has become one of the most common cancers and has a high mortality rate. Hepatocellular carcinoma is one of the most common liver cancers, and its occurrence and development process are associated with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. Main body The serious consequences of chronic hepatitis virus infections are related to the viral invasion strategy. Furthermore, the viral escape mechanism has evolved during long-term struggles with the host. Studies have increasingly shown that suppressor of cytokine signaling (SOCS) proteins participate in the viral escape process. SOCS proteins play an important role in regulating cytokine signaling, particularly the Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling pathway. Cytokines stimulate the expression of SOCS proteins, in turn, SOCS proteins inhibit cytokine signaling by blocking the JAK-STAT signaling pathway, thereby achieving homeostasis. By utilizing SOCS proteins, chronic hepatitis virus infection may destroy the host's antiviral responses to achieve persistent infection. CONCLUSIONS: This review provides recent knowledge regarding the role of SOCS proteins during chronic hepatitis virus infection and provides some new ideas for the future treatment of chronic hepatitis.

Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation.

BACKGROUND: Human loss-of-function variants of ANK2 (ankyrin-B) are linked to arrhythmias and sudden cardiac death. However, their in vivo effects and specific arrhythmogenic pathways have not been fully elucidated. METHODS: We identified new ANK2 variants in 25 unrelated Han Chinese probands with ventricular tachycardia by whole-exome sequencing. The potential pathogenic variants were validated by Sanger sequencing. We performed functional and mechanistic experiments in ankyrin-B knockin (KI) mouse models and in single myocytes isolated from KI hearts. RESULTS: We detected a rare, heterozygous ANK2 variant (p.Q1283H) in a proband with recurrent ventricular tachycardia. This variant was localized to the ZU5C region of ANK2, where no variants have been previously reported. KI mice harboring the p.Q1283H variant exhibited an increased predisposition to ventricular arrhythmias after catecholaminergic stress in the absence of cardiac structural abnormalities. Functional studies illustrated an increased frequency of delayed afterdepolarizations and Ca2+ waves and sparks accompanied by decreased sarcoplasmic reticulum Ca2+ content in KI cardiomyocytes on isoproterenol stimulation. The immunoblotting results showed increased levels of phosphorylated ryanodine receptor Ser2814 in the KI hearts, which was further amplified on isoproterenol stimulation. Coimmunoprecipitation experiments demonstrated dissociation of protein phosphatase 2A from ryanodine receptor in the KI hearts, which was accompanied by a decreased binding of ankyrin-B to protein phosphatase 2A regulatory subunit B56α. Finally, the administration of metoprolol or flecainide decreased the incidence of stress-induced ventricular arrhythmias in the KI mice. CONCLUSIONS: ANK2 p.Q1283H is a disease-associated variant that confers susceptibility to stress-induced arrhythmias, which may be prevented by the administration of metoprolol or flecainide. This variant is associated with the loss of protein phosphatase 2A activity, increased phosphorylation of ryanodine receptor, exaggerated delayed afterdepolarization-mediated trigger activity, and arrhythmogenesis.

FAT10 attenuates hypoxia-induced cardiomyocyte apoptosis by stabilizing caveolin-3.

FAT10, a member of the ubiquitin-like-modifier family of proteins, plays a cardioprotective role in response to hypoxic/ischemic injury. Caveolin-3 (Cav-3), a muscle-specific caveolin family member, is involved in cardiomyocyte apoptosis. However, the link between FAT10 and Cav-3 in ischemic cardiomyocytes is unclear. In the present study, we found that both FAT10 and Cav-3 were upregulated in ischemic myocardial tissues and in hypoxic cardiomyocytes. Furthermore, our results demonstrated that FAT10 inhibits hypoxia-induced cardiomyocyte apoptosis by increasing Cav-3 expression. Importantly, following myocardial infarction, knockout of FAT10 aggravated cardiac dysfunction and increased cardiomyocyte apoptosis by reducing Cav-3 expression. Additionally, Cav-3 was degraded by the ubiquitin-proteasome system (UPS) in cardiomyocytes. Mechanistically, we found that FAT10 stabilizes Cav-3 expression by inhibiting ubiquitination-mediated degradation in cardiomyocytes. Together, these findings revealed a novel role of FAT10 in protection against ischemia-induced injury via stabilization of Cav-3, providing evidence that the FAT10/Cav-3 axis may be a potential therapeutic target for patients with ischemic heart conditions.

A Review of Emotion Recognition Using Physiological Signals.

Emotion recognition based on physiological signals has been a hot topic and applied in many areas such as safe driving, health care and social security. In this paper, we present a comprehensive review on physiological signal-based emotion recognition, including emotion models, emotion elicitation methods, the published emotional physiological datasets, features, classifiers, and the whole framework for emotion recognition based on the physiological signals. A summary and comparation among the recent studies has been conducted, which reveals the current existing problems and the future work has been discussed.

[NMDA receptor and its role in cardiovascular diseases].

Cardiovascular disease is the main threat to human health, which is one of the important causes of death in worldwide. N-methyl-D-aspartate receptor (NMDAR) is one of crucial ionic glutamate receptors. The physiology and pharmacology function of the composition of NMDAR are very complicated. Researches have shown that NMDAR with a high permeability to calcium and a unique feature of controlling numerous calcium-dependent processes. NMDAR affects the occurrence and development of cardiovascular disease such as hypertension, arrhythmia, myocardial infarction.

Genotype-based clinical manifestation and treatment of Chinese long QT syndrome patients with KCNQ1 mutations - R380S and W305L.

UNLABELLED: Aim Most long QT syndrome patients are associated with genetic mutations. We aimed to investigate the clinical and biochemical characteristics and look for genotype-based preventive implications in Chinese long QT syndrome patients. Methods and results We identified two missense mutations of the KCNQ1 gene in two independent Chinese families, including a previously reported mutation R380S in the C-terminus and a novel mutation W305L in the P-loop domain of the Kv7.1 channel, respectively. The proband with R380S was an 11-year-old girl who suffered a prolonged corrected QT interval of 660 ms, recurrent syncope, and sudden cardiac death, whose father was an asymptomatic carrier. The mutation W305L was detected in a 36-year-old woman with long QT syndrome and her immediate family members including the proband's younger sister with an unexplained syncope, her son, and her elder daughter without symptoms. Metoprolol appeared to be effective in preventing arrhythmias and syncope in long QT syndrome patients with mutation W305L. Both R380S and W305L mutations led to "loss-of-function" of the Kv7.1 channel accounting for the clinical phenotypes. CONCLUSIONS: We first show two missense KCNQ1 mutations - R380S and W305L - in Chinese long QT syndrome patients, resulting in the loss of protein function. Mutation W305L in the P-loop domain of the Kv7.1 may derive a pronounced benefit from ß-blocker therapy in symptomatic long QT syndrome patients, whereas mutation R380S located in the C-terminus may be associated with a high risk of sudden cardiac death.

[High incidence of sudden cardiac death in one family with type-3 long QT syndrome: molecular genetics and electrophysiology mechanism analysis].

OBJECTIVES: We identified the long QT syndrome (LQTS) patients, and detected the potential risk of LQTS in family members by using genetic testing and electrophysiological analysis, which helped provide clinical evaluation and appropriate treatment. METHODS: Detailed clinical characteristics and familiar history were obtained from the whole family members of an idiopathic pediatric LQTS patient. Two hundred healthy subjects with the same ethnic background were recruited as controls. The entire coding sequences of three candidate genes including KCNQ1, KCNH2 and SCN5A were screened for mutations in the proband. The function of the mutation was then explored by whole-cell patch clamp techniques, and the genetic testing and risk assessment of the family members were performed. RESULTS: The proband was clinically preliminary diagnosed as LQTS by 12-lead electrocardiogram. On the third day of metoprolol intake (25 mg, bid), she died suddenly at lunch. One heterozygous missense mutation (SCN5A-V411M) was identified in this proband, but the mutation was absent in 200 healthy subjects. The electrophysiological analysis indicated that SCN5A-V411M significantly increased the peak current density ((230.8 ± 27.6)pA/pF vs. (101.2 ± 10.9)pA/pF, n=10, P<0.01) and the late sodium current ((156.6 ± 13.6)pA/pF vs. (95.9 ± 7.9)pA/pF, n=12, P<0.01) of sodium channel compared to wide type. The enhanced sodium channel activation with a negative shift in the peak I-V relationship was significantly higher by -50 mV than wide type (85.0%± 7.4% vs. 41.5% ± 2.6%, P<0.01), while the steady-state inactivation curves remained unchanged. Additionally, mother and grandmother of the proband were the silent mutation carriers with no symptoms, who needed the appropriate clinical assessment and follow-up. The proband's twin sister and aunt died of sudden infant death syndrome. CONCLUSIONS: We firstly reported a heterozygote missense mutation (SCN5A-V411M) in this Chinese family. V411M induced "gain of function" of sodium channel and formed the basis of type-3 LQTS. Genetic testing could help to increase the diagnostic accuracy, and facilitate clinical assessment and appropriate therapy to prevent sudden cardiac death of individuals with SCN5A-V411M mutation.

Expression profile of mitrogen-activated protein kinase (MAPK) signaling genes in the skeletal muscle & liver of rat with type 2 diabetes: role in disease pathology.

BACKGROUND & OBJECTIVES: Type 2 diabetes (T2D) is characterized as hyperglycaemia caused by defects in insulin secretion, and it affects target tissues, such as skeletal muscle, liver and adipose tissue. Therefore, analyzing the changes of gene expression profiles in these tissues is important to elucidate the pathogenesis of T2D. We, therefore, measured the gene transcript alterations in liver and skeletal muscle of rat with induced T2D, to detect differentially expressed genes in liver and skeletal muscle and perform gene-annotation enrichment analysis. METHODS: In the present study, skeletal muscle and liver tissue from 10 streptozotocin-induced diabetic rats and 10 control rats were analyzed using gene expression microarrays. KEGG pathways enriched by differentially expressed genes (DEGs) were identified by WebGestalt Expander and GATHER software. DEGs were validated by the method of real-time PCR and western blot. RESULTS: From the 9,929 expressed genes across the genome, 1,305 and 997 differentially expressed genes (DEGs, P<0.01) were identified in comparisons of skeletal muscle and liver, respectively. Large numbers of DEGs (200) were common in both comparisons, which was clearly more than the predicted number (131 genes, P<0.001). For further interpretation of the gene expression data, three over-representation analysis softwares (WebGestalt, Expander and GATHER) were used. All the tools detected one KEGG pathway (MAPK signaling) and two GO (gene ontology) biological processes (response to stress and cell death), with enrichment of DEGs in both tissues. In addition, PPI (protein-protein interaction) networks constructed using human homologues not only revealed the tendency of DEGs to form a highly connected module, but also suggested a "hub" role of p38-MAPK-related genes (such as MAPK14) in the pathogenesis of T2D. INTERPRETATION & CONCLUSIONS: Our results indicated the considerably aberrant MAPK signaling in both insulin-sensitive tissues of T2D rat, and that the p38 may play a role as a common "hub" in the gene module response to hyperglycaemia. Furthermore, our research pinpoints the role of several new T2D-associated genes (such as Srebf1 and Ppargc1) in the human population.

Evodiamine activates AMPK and promotes adiponectin multimerization in 3T3-L1 adipocytes.

Adiponectin, an adipokine with insulin-sensitizing effect, is secreted from adipocytes into circulation as high, medium, and low molecular weight (HMW, MMW, and LMW) forms. The HMW adiponectin is more metabolically active and the ratio of HMW adiponectin to total adiponectin directly correlates with insulin sensitivity. Evodiamine is an indole alkaloid found in the traditional Chinese medicinal plant Evodia rutaecarpa. In this study, evodiamine was found to activate AMP-activated protein kinase (AMPK) in both 3T3-L1 adipocytes and 293T cells. Activation of AMPK by evodiamine promoted the assembly of HMW adiponectin and increased the HMW/total ratio of adiponectin in 3T3-L1 adipocytes. The Ca(2+)-dependent PI3K/Akt/CaMKII-signaling pathway was demonstrated to be involved in evodiamine-induced AMPK activation. This study revealed a novel role of this Ca(2+)-mediated signaling pathway in promoting the multimerization of adiponectin.

Discovery from Hypericum elatoides and synthesis of hyperelanitriles as α-aminopropionitrile-containing polycyclic polyprenylated acylphloroglucinols.

The search for lead compounds with anti-neuroinflammatory activity from structurally 'optimized' natural products is a crucial and promising strategy in the quest to discover safe and efficacious agents for treating neurodegenerative diseases. A phytochemical investigation on the aerial portions of Hypericum elatoides led to the isolation of five nitrogenous polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperelanitriles A-D (1-4) and hyperelamine A (5). Their structures were determined by spectroscopic analysis, ECD and NMR calculations, and X-ray crystallography. To the best of our knowledge, compounds 1-4 represent the first examples of acylphloroglucinols featuring an α-aminonitrile moiety, while 5 is a rare enamine-containing PPAP. Further, the synthesis of these naturally occurring PPAP-based nitriles or amines was accomplished. Compound 5 exhibited inhibitory activity against LPS-activated NO production in BV-2 cells, potentially through the suppression of TLR-4/NF-κB signaling. Here we show the isolation, structural elucidation, synthesis, and bioactive evaluation of compounds 1-5.

ACLS4 could be a potential therapeutic target for severe acute pancreatitis.

Acute pancreatitis (AP) is currently among the most prevalent digestive diseases. The pathogenesis of AP remains elusive, and there is no specific treatment. Therefore, identifying novel therapeutic targets is imperative for effective management and prevention of AP. In this study, we conducted a comprehensive transcriptomic analysis of peripheral blood from patients with AP and the pancreatic tissue from a mouse model of AP. Our analyses revealed that mouse model of AP exhibited a higher enrichment of mitogen-activated protein kinase signaling, endocytosis, apoptosis and tight junction pathways than the control. Subsequent weighted gene co-expression network analysis identified 15 gene modules, containing between 50 and 1000 genes each, which demonstrated significant correlations within samples from patients with AP. Further screening identified four genes (ACSL4, GALNT3, WSB1, and IL1R1) that were significantly upregulated in severe acute pancreatitis (SAP) in both human and mouse samples. In mouse models of SAP, ACSL4 was significantly upregulated in the pancreas, whereas GALNT3, WSB1, and IL1R1 were not. Lastly, we found that a commercially available ACSL4 inhibitor, PRGL493, markedly reduced IL-6 and TNFα expression, alleviated pancreatic edema and necrosis, and diminished the infiltration of inflammatory cells. In conclusion, this study comprehensively depicts the key genes and signaling pathways implicated in AP and suggests the potential of ACSL4 as a novel therapeutic target for SAP. These findings provide valuable insights for further exploration of therapeutic strategies for SAP.

The association between procrastination in academic writing and negative emotional states during the COVID-19 pandemic: the indirect effects of stress coping styles and self-efficacy.

BACKGROUND AND OBJECTIVES: Limited research has examined the mediating mechanisms underlying the association between procrastination in academic writing and negative emotional states during the COVID-19 pandemic. In the present study, we examined whether stress coping styles and self-efficacy for self-regulation of academic writing mediated the relationship between procrastination in academic writing and negative emotional states. DESIGN AND METHOD: Graduate students (N = 475, 61.7% female, Mage of students at baseline = 29.02 years, SD = 5.72) completed questionnaires at Time 1 (March 2020; Procrastination in Academic Writing and Coping Inventory for Stressful Situations), and Time 2 (June 2020; The Self-Efficacy for Self-Regulation of Academic Writing Scale and Depression, Anxiety, and Stress Scale - 21). RESULTS: Emotion-oriented coping and the self-efficacy for self-regulation of academic writing serially mediated the association between procrastination in academic writing and negative emotional states. Meanwhile, task-oriented coping and self-efficacy for self-regulation of academic writing also serially mediated the association between procrastination in academic writing and negative emotional states. CONCLUSIONS: These findings provide a plausible explanation of the roles that stress coping styles and self-efficacy for self-regulation of academic writing play in the association between procrastination in academic writing and negative emotional states.

Comprehensive prognostic and immunological analysis of Cullin2 in pan-cancer and its identification in hepatocellular carcinoma.

BACKGROUND: As a member of the Cullin family, Cullin2 (CUL2) is involved in the development and spread of different types of cancers. However, the precise role of CUL2 in human cancer remains largely elusive. METHODS: In this study, various databases were applied to observe the CUL2 expression. Kaplan-Meier and Spearman correlation analyses were employed to investigate the potential links between CUL2 level, patient prognosis, and the infiltration of immune cells. In addition, the association between CUL2 and the efficacy of immunotherapy in an immunotherapy cohort was investigated. Moreover, the expression and distribution of CUL2 in cells were observed using the Human Protein Atlas (THPA) database. Finally, clinical tissue specimens and in vitro function assays were conducted to validate the expressions and effects of CUL2 on the biological functions in hepatocellular carcinoma (HCC) cells. RESULTS: While there are variations in CUL2 expression across different organs and cell types, it is notably upregulated in a majority of tumor tissues. In addition, CUL2 gene mutations are common in multiple cancers with low mutation rates and CUL2 is closely related to the prognosis of some cancer's patients, some immune regulatory factors, TMB, MSI, MMR genes, and DNA methylation. Further, our results found that downregulating CUL2 inhibits the proliferation, and migration abilities. CONCLUSIONS: The expression of CUL2 has an impact on the prognosis of various tumors, and this correlation is particularly noteworthy due to its significant association with the infiltration of immune cells within tumors. CUL2 was an oncogene contributing to the progression of HCC.

HIV-1 envelope protein gp120 modulation of glutamate effects on cortical neuronal synapses: implications for HIV-1-associated neuropathogenesis.

Despite the introduction of combined antiretroviral therapy (cART) HIV-1 virus persists in the brain in a latent or restricted manner and viral proteins, such as gp120, continue to play a significant disease-inciting role. Gp120 is known to interact with N-methyl-D-aspartate (NMDA) receptors (NMDARs) resulting in neuronal injury. Glutamate is the main excitatory neurotransmitter in the brain and plays an important role in cognitive function and dysregulation of excitatory synaptic transmission impairs neurocognition. It is our hypothesis that gp120 may alter synaptic function via modulating glutamate function from a physiological molecule to a pathophysiological substance. To test this hypothesis, we studied the modulatory effects of gp120 and glutamate on NMDAR-mediated spontaneous excitatory postsynaptic current (sEPSCNMDAR) and dynamic dendritic spine changes in rat cortical neuronal cultures. Our results revealed that gp120 and glutamate each, at low concentrations, had no significant effects on sEPSCNMDAR and dendritic spines, but increased sEPSCNMDAR frequency, decreased numbers of dendritic spines when tested in combination. The observed effects were blocked by either a CXCR4 blocker or an NMDAR antagonist, indicating the involvements of chemokine receptor CXCR4 and NMDARs in gp120 modulation of glutamate effects. These results may imply a potential mechanism for HIV-1-associated neuropathogenesis in the cART era.